- OSA triples the risk of risk of incident hypertension over a period of 4 years [5]

- 70-83% of patients with drug-resistant hypertension have OSA [6]

- 70% of patients with Type 2 diabetes have sleep apnea (ASAA)

- SDB is present in 77% of men and 64% of women with a history of stroke, 76% of individuals with congestive heart failure and 60% of patients with metabolic syndrome [7,8,9]

- The rate of motor vehicle accidents is seven times higher in patients with sleep apnea than in the average population [10]

Sleep Apnea: Understanding the Cardiometabolic Vicious Cycle

by Liana Groza, DDSMarch 30, 2015

The major consequences of obstructive sleep apnea (OSA) include cardiac rhythm abnormalities; hypertension, which is often resistant to medication; intravascular inflammation, which has been linked to a significantly higher risk of heart attack and stroke; and metabolic disturbances, including insulin resistance. As a result, sleep apnea is often one of the main components in the vicious circle connecting obesity, diabetes, cardiovascular disease and stroke.

Diabetes and Insulin Resistance: Both the Sleep Heart Health Study and the Wisconsin Sleep Cohort Study have found an independent association between insulin resistance/ diabetes and OSA in patients who report excessive daytime sleepiness (Ronksley et al. 2009). While obesity is a major determinant of insulin resistance (IR), OSA has been shown to act as an additional, independent risk factor for IR. Both obese and non-obese subjects with diagnosed sleep apnea show higher insulin resistance - with each additional apnea or hypopnea per sleep hour increasing the fasting insulin level by about 0.5% (Manzella et al, 2002).

Body Weightis difficult to control in the presence of sleep apnea, because OSA triggers a dysregulation in the serum leptin levels (a critical hormone controlling energy expenditure, body weight and fat distribution). A 10% weight gain increases the risk of moderate to severe OSA by a factor of 6 and is associated with a 32% increase in the AHI index (Peppard et al 2000). Effective CPAP treatment tends to restore leptin concentrations and shift the hormonal control of body weight toward a normal balance (Phillips et al, 2000).

Systemic Inflammation: Patients with sleep apnea demonstrate increased concentrations of the inflammatory cytokines TNF-alpha and IL-6, which cause fatigue and insulin resistance (Manzella et al, 2002). Another inflammatory marker that is elevated in patients with OSA is CRP (C-reactive protein), an indicator of future heart attack or stroke risk. In OSA patients, CRP levels have been shown to correlate significantly with the severity of sleep apnea (Shamsuzzaman, et al, 2002).

Hypertension in patients with OSA is due to the repetitive episodes of apnea, hypoxia and arousal during sleep, which maintain the body in a state of constant stress and sympathetic drive activation. In time this leads to a dysfunction in normal regulatory mechanisms, resulting in persistent high sympathetic drive which is present even during normal daytime wakefulness and breathing (Kato et al, 2009). CPAP treatment as well as effective treatment with oral appliances have been shown to reduce OSA-associated hypertension to a similar degree (Van Haesendonck et al, 2015, Wilcox et al, 1993). 30-40% of patients with high blood pressure and a striking 83% of patients (96% of males) with drug-resistant hypertension have been shown to suffer from obstructive sleep apnea (ASAA, Logan et al, 2001). In such cases, where 3 or more anti-hypertensive medications fail to reduce the blood pressure below 140/90, a sleep study should be strongly considered.

Cardiac Arrhythmia: cardiac rhythm abnormalities are common in sleep apnea, including significantly higher rates of bradycardia, sinoatrial block and paroxysmal supraventricular tachycardia (Namtvedt 2011, Roche et al. 2003) . These are due to the OSA-induced hypoxemia, hypercapnia and acidosis, as well as the increase in sympathetic stress response. There is a strong association between atrial fibrillation (AF), which is a risk factor for stroke, and OSA. 32-49% of patients with AF have been shown to have sleep apnea (Gami 2005), which increases the likelihood of AF recurrence following treatment; treatment with CPAP appears to substantially reduce the frequency and post-ablation recurrence of AF (Dimitri et al 2012; Fein et al 2013; Hoyer at al 2010; Matiello et al 2010; Ng et at 2011).

Cardiovascular Disease: severe sleep apnea is associated with a 5-fold increase in the risk of cardiovascular mortality (Young et al 2008). The repeated cycles of intermittent hypoxia, arousal and reoxygenation associated with OSA produce elevated levels of reactive oxygen species, which have been shown to cause systemic inflammation, endothelial damage and an increased expression of adhesion molecules, triggering the formation of atherosclerotic plaque and contributing to hypertension (Hayashi 2003). The chronically high levels of systemic inflammation in OSA patients are a known major risk factor for heart attack and stroke, as inflammation leads to atherosclerotic plaque rupture and thromboembolic events (Mangge et al 2014; Murray at al 2013; Thompson et al 2013).

Stroke: Obstructive sleep apnea more than doubles the risk of stroke in men (NIH 2010). Snoring also shows a high correlation with stroke - in fact the likelihood of a stroke is greater in patients who snore than those who smoke (Spriggs 1990). Patients with moderate to severe OSA have a higher incidence of silent strokes than those with milder or no OSA (Minoguchi 2007; Nishibayashi 2008). Multiple mechanisms are likely implicated, but one of the primary contributors is systemic inflammation - with OSA patients consistently showing elevated levels of TNF-alpha, Interleukin-6, CRP and increased carotid intima-media thickness (Minoguchi et al 2007).

Brain Changes, Neurocognitive Effects and Dementia: Levels of Serum Amyloid A (SAA), which has been linked to the development of atherosclerosis, stroke, diabetes and dementia, are more than doubled in patients with moderate to severe OSA, compared to mild OSA or healthy controls (Svatikova et al. 2003).

OSA is associated with neurocognitive impairment, especially in measures of concentration, short- and long-term memory, executive and motor function. CPAP treatment has been shown to produce significant improvements, especially in memory and executive function. Children with OSA show difficulty with sustained attention and behavior, and the severity of the OSA correlates with measures of verbal ability. Younger patients with sleep apnea also scored lower on IQ tests than patients without OSA (Beebe et al 2003; Cassel et al. 1989; Verstraeten 2007).

In a study of patients with moderate to severe apnea, extensive white matter changes were found, indicating myelin loss or damage in brain areas controlling mood, cognition, cardiovascular regulation and breathing control (Macey 2008 ). Gray matter loss and reduced metabolism were also found in multiple areas, primarily in the right hemisphere, as was a reduced cerebral blood flow while awake (Hajak 1995; Kneisley 1993; Yaouhi 2009). An additional implication of these OSA-related neurological changes is that the presence of untreated sleep apnea in patients with a history of stroke makes recovery more challenging (Ryan 2011).

Pregnancy: Because of physiological and hormonal changes, pregnant women are at higher risk for developing or worsening sleep disordered breathing (Venkata and Venkateshiah 2009). Pregnant women with sleep disordered breathing have more than double the rates of hypertension and pre-eclampsia compared to non-snorers, and significantly higher risk of fetal growth retardation (Franklin et al. 2000). OSA is also associated with an increase in pre-term births (mostly as a results of preeclampsia), lower Apgar scores and birth weights as well as maternal medical complications (Louis et al 2010; Sahin et al 2008).

Conclusion

Sleep Apnea is a complex, many-faceted condition that is affected by and in turn impacts some of the most prevalent chronic morbidities in the developed world - such as diabetes, cardiovascular disease and stroke. Because many of these conditions share common causes and pathophysiological mechanisms, it is often difficult to successfully control them by addressing only one contributing risk at a time. This complex interplay of learned behaviors (an unhealthy diet, poor sleep habits and sedentary lifestyle), the physiological changes they trigger (such as systemic inflammation, insulin resistance, sleep apnea, altered leptin and other hormonal levels, adverse changes in endothelial function and vascular physiology) and the resultant reinforcement of unhealthy behaviors (reduced exercise and increased appetite due to low energy as a consequence of poor sleep and hormonal balance alterations) makes it imperative that patients and their health care teams understand every component of this vicious circle and formulate a comprehensive, specific plan of action to address each root cause simultaneously.

Manzella, D., et al. "Soluble leptin receptor and insulin resistance as determinant of sleep apnea." International journal of obesity and related metabolic disorders: journal of the International Association for the Study of Obesity 26.3 (2002): 370-375.